Comparison of Nasal Potential Difference and Intestinal Current Measurements as Surrogate Markers for CFTR Function.

OBJECTIVES: Nasal potential difference (NPD) measurement is part of the diagnostic criteria for cystic fibrosis (CF) and now used routinely as an endpoint in clinical trials of correcting the basic defect in CF. Intestinal current measurement (ICM), measured ex vivo on a rectal biopsy, has been used to study cystic fibrosis transmembrane conductance regulator (CFTR) function but has not been compared to NPD in the same subject in adults and children. The aim of the study is to evaluate the potential usefulness of ICM as a marker of CFTR function for treatment studies compared NPD in patients with CF and in healthy control subjects. METHODS: ICM and NPD were performed on healthy controls and patients with CF. The healthy adults were individuals undergoing routine screening colonoscopy at the Beth Israel Deaconess Medical Center. The healthy children were undergoing colonoscopy for suspicion of inflammation in Hadassah Hebrew University Medical Center. The CF adults were recruited from Boston Children's Hospital CF Center and CF Center Worcester Mass, the children with CF from Hadassah CF Center. RESULTS: ICM measurements in healthy control subjects (n = 16) demonstrated a mean (±SE) carbachol response of 16.0 (2.2) µA/cm, histamine response of 13.2 (2.1) µA/cm and a forskolin response of 6.3 (2.0) µA/cm. Basal NPD of -15.9 (1.9) and response to Cl free + isoproterenol of -13.8 (2.0). These responses were inverted in CF subjects (n = 12) for ICM parameters with carbachol response of -3.0 (0.5) µA/cm, histamine -1.0 (0.8) µA/cm and a forskolin response of 0.5 (0.3) and also for NPD parameters; basal NPD of -42.2 (4.3) and response to Cl free + isoproterenol of 4.3 (0.7). Pearson correlation test showed the comparability of ICM and NPD in assessing CFTR function. CONCLUSIONS: ICM is equivalent to NPD in the ability to distinguish patients with CF from controls and could be used as surrogate markers of CFTR activity in treatment protocols.

Factors Determining Optimal Fatty Acid Absorption in Preterm Infants.

OBJECTIVES: The aim of the present study was to quantify absorption coefficients of specific fatty acids in preterm infants as a function of diet, formula or breast milk (BM), and postnatal age; to identify the fatty acid structural characteristics that determine optimal fatty acid absorption. METHODS: Fatty acids from dietary and fecal samples were extracted and quantified by gas chromatography-mass spectroscopy. Fatty acid absorption coefficients (FA-CFAs) were calculated by comparing the total amount of fatty acids supplied by the diet to the amount quantified in the total fecal output during a 3-day period. RESULTS: A total of 18 infants (BM 8, formula 10) were studied at 2 weeks of age, and 20 infants (BM 10, formula 10) were studied at 6 weeks of age. FA-CFAs decreased with increasing carbon length in formula-fed infants at 2 and 6 weeks. Results were similar but less in magnitude in BM-fed infants at 2 weeks with no difference at 6 weeks. CONCLUSIONS: Preterm infants fed formula demonstrated lower FA-CFAs as a function of increasing carbon length. This is consistent with limited pancreatic lipase production and with lipase being present in BM but not in formula. The fact that this pattern was seen in BM-fed infants at 2 weeks but not 6 weeks of age suggests that intestinal immaturity may also play a role in impaired fatty acid absorption. These data highlight principles that need to be considered to optimize delivery and absorption of dietary long-chain polyunsaturated fatty acids in preterm infants.

Defining the accuracy of secretin pancreatic function testing in patients with suspected early chronic pancreatitis.

OBJECTIVES: The diagnosis of chronic pancreatitis in patients with characteristic symptoms but normal pancreatic imaging is challenging. Assessment of pancreatic function through secretin pancreatic function testing (SPFT) has been advocated in this setting, but its diagnostic accuracy is not fully known. METHODS: This was a retrospective review of patients who received SPFT at our tertiary care institution between January 1995 and December 2008 for suspected chronic pancreatitis. For all patients, medical records were reviewed for evidence of subsequent development of chronic pancreatitis by imaging and/or pathology. Patients were then categorized as "true positive" or "true negative" for chronic pancreatitis based on follow-up imaging or histologic evidence. RESULTS: In all, 116 patients underwent SPFT. Of the 27 patients who tested positive, 7 were lost to follow-up. Of the remaining 20 SPFT-positive patients, 9 (45%) developed radiologic or histologic evidence of chronic pancreatitis after a median of 4 years (1-11 years). Of the 89 patients who had negative SPFT testing, 19 were lost to follow-up. Of the remaining 70 patients, 2 were eventually diagnosed with chronic pancreatitis based on subsequent imaging/histology after a median follow-up period of 7 years (3-11 years). The sensitivity of the SPFT in diagnosing chronic pancreatitis was 82% with a specificity of 86%. The positive predictive value (PPV) of chronic pancreatitis was 45% with a negative predictive value (NPV) of 97%. CONCLUSIONS: In patients with suspected early chronic pancreatitis and normal pancreatic imaging, SPFT is highly accurate at ruling out early chronic pancreatitis with a NPV of 97%.

Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities.

OBJECTIVE: To measure the changes in whole blood fatty acid levels in premature infants and evaluate associations between these changes and neonatal morbidities. STUDY DESIGN: This was a retrospective cohort study of 88 infants born at <30 weeks' gestation. Serial fatty acid profiles during the first postnatal month and infant outcomes, including chronic lung disease (CLD), retinopathy of prematurity, and late-onset sepsis, were analyzed. Regression modeling was applied to determine the association between fatty acid levels and neonatal morbidities. RESULTS: Docosahexaenoic acid (DHA) and arachidonic acid levels declined rapidly in the first postnatal week, with a concomitant increase in linoleic acid levels. Decreased DHA level was associated with an increased risk of CLD (OR, 2.5; 95% CI, 1.3-5.0). Decreased arachidonic acid level was associated with an increased risk of late-onset sepsis (hazard ratio, 1.4; 95% CI, 1.1-1.7). The balance of fatty acids was also a predictor of CLD and late-onset sepsis. An increased linoleic acid:DHA ratio was associated with an increased risk of CLD (OR, 8.6; 95% CI, 1.4-53.1) and late-onset sepsis (hazard ratio, 4.6; 95% CI, 1.5-14.1). CONCLUSION: Altered postnatal fatty acid levels in premature infants are associated with an increased risk of CLD and late-onset sepsis.

Clinical effects and brain metabolic correlates in non-invasive cortical neuromodulation for visceral pain.

BACKGROUND AND AIMS: Chronic visceral pain is frequent, extremely debilitating, and generally resistant to pharmacological treatment. It has been shown that chronic visceral inflammation, through altered afferent visceral sensory input, leads to plastic changes in the central nervous system that ultimately sustain pain. Therefore approaches aiming at modulation of brain activity are attractive candidates to control visceral pain. METHODS: Here we report findings of a phase II, sham-controlled clinical trial assessing the clinical effects and brain metabolic correlates of a 10-day course of daily sessions of slow-frequency, repetitive transcranial magnetic stimulation (rTMS) targeting the right secondary somatosensory cortex (SII) in patients with chronic pancreatitis and severe visceral pain. RESULTS: Our results show a significant reduction in pain after real rTMS that lasted for at least 3 weeks following treatment. These clinical changes were correlated with increases in glutamate and N-acetyl aspartate (NAA) levels--neurometabolites associated with cortical activity and brain damage--as measured by in vivo single-voxel proton magnetic resonance spectroscopy (1H-MRS). Adverse effects in the real rTMS group were mild and short-lasting. CONCLUSIONS: Our results support preliminary findings showing that modulation of right SII with rTMS is associated with a significant analgesic effect and that this effect is correlated with an increase in excitatory neurotransmitter levels such as glutamate and NAA.

Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function.

OBJECTIVE: To determine whether primary sclerosing cholangitis (PSC) in childhood is associated with abnormalities in cystic fibrosis transmembrane conductance regulator (CFTR). STUDY DESIGN: Subjects with PSC diagnosed in childhood (n = 20) were recruited from Children's Hospital. Subjects had testing with sweat chloride concentration, nasal transmembrane potential difference, and extensive genetic analysis of the CFTR gene. Disease control subjects consisted of 14 patients with inflammatory bowel disease alone and no liver disease. t tests were performed to determine statistical significance. RESULTS: In the PSC group, CFTR chloride channel function (deltaChloride free + isoproterenol) was markedly diminished at -8.6 +/- 8.2 mV (reference range: -24.6 +/- 10.4 mV). In contrast, disease control subjects had normal function, at -17.8 +/- 9.7 mV (P = .008). Sweat chloride concentration in subjects with PSC was greater than in disease control subjects (20.8 +/- 3.4 mmol/L vs 12.0 +/- 1.6 mmol/L, P = .045). Comprehensive CFTR genotyping revealed that 5 of 19 (26.3%) subjects with PSC had a CFTR mutation or variant, compared with 6 of 14 (42.9%) disease control subjects. CONCLUSIONS: There is a high prevalence of CFTR-mediated ion transport dysfunction in subjects with childhood PSC.